Citations

Abstract Characterizing intra- and inter-tumoral heterogeneity of glioblastoma has historically relied on discrete classifications of malignant cell populations leaving immune and other cell populations, known to exist admixed with the malignant tumor cells, relatively neglected. Manifold learning algorithms can manage deconvolving multiple cell populations and are often used to track cell state transitions in single cell transcriptomics. We applied a manifold learning approach to TCGA microarray data (Nf525) and bulk transcriptomics of 134 image localized biopsies across 30 patients with primary and 9 with recurrent glioblastoma to further elucidate how to organize biopsies across a spectrum of possible tissue states. The algorithm revealed a low-dimensional manifold graph for which each biopsy lives across 3 polarizing tissue states - one that is associated with diffusely invaded brain, one that is enriched in mesenchymal genes, and one that is enriched in classical proliferative tumor signatures. We deconvolved the bulk transcriptomics of the image-localized biopsies to reveal the relative abundance of 18 malignant, immune, and other cell subpopulations in each biopsy. Overlaying the cellular decomposition onto the manifold graph visualizing the tissue state distributions revealed that transitions between states correlate with changes in cellular cohabitation composition. The tumor cellular cohabitation ecologies have the lowest diversity, as inferred by ecological measures such as Shannon entropy and evenness, at the distal poles of the graph when compared to the transitional arms. Further, we found that the relationship between imaging appearance of contrast enhancement on T1-weighted MRI and the biopsy cellular composition varies with sex and primary vs recurrent biopsy status. The limited spectrum of possible tissue states revealed by the manifold learning is suggestive of a limited continuum along which tumor and non-tumoral cell populations can cohabitate. Such a limited low-dimensional biological space may constrain the dynamics of tumor biology in a predictable manner.

AbstractTransthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Background: Hybrid debranching repair of pararenal and thoracoabdominal aortic aneurysms was initially designed as a better alternative to standard open repair, addressing the limitations of endovascular repair involving the visceral aorta. We reviewed the collective outcomes of hybrid debranching repairs using extra-anatomic, open surgical debranching of the renal-mesenteric arteries, followed by endovascular aortic stenting. Methods: Data from patients who underwent hybrid repair in 14 North American institutions during 10 years were retrospectively reviewed. Society of Vascular Surgery scores were used to assess comorbidity risk. Early and late outcomes, including mortality, morbidity, reintervention, and patency were analyzed. Results: A total of 208 patients (118 male; mean age, 71±8 years old) were treated by hybrid repair with extraanatomic reconstruction of 657 renal and mesenteric arteries (mean 3.2 vessels/patient). Mean aneurysm diameter was 6.6±1.3 cm. Thoracoabdominal aortic aneurysms were identified in 163 (78%) patients and pararenal aneurysms in 45 (22%). A single-stage repair was performed in 92 (44%) patients. The iliac arteries were the most common source of inflow (n=132; 63%), and most (n=150; 72%) had 3 or more bypasses. There were 30 (14%) early deaths, ranging widely across sites (0%–21%). A Society of Vascular Surgery comorbidity score >15 was the primary predictor of early mortality ( P <0.01), whereas mortality was 3% in a score ≤9. Early complications occurred in 140 (73%) patients and included respiratory complications in 45 patients (22%) and spinal cord ischemia in 22 (11%), of whom 10 (45%) fully recovered. At 5 years, survival was 61±5%, primary graft patency was 90±2%, and secondary patency was 93±2%. The most significant predictor of late mortality was renal insufficiency ( P <0.0001). Conclusions: Mortality after hybrid repair and visceral debranching is highly variable by center, but strongly affected by preoperative comorbidities and the centers’ experience with the technique. With excellent graft patency at 5 years, the outcomes of hybrid repair done at centers of excellence and in carefully selected patients may be comparable (or better) than traditional open or even totally endovascular approaches. However, in patients already considered as high-risk for surgery, it may not offer better outcomes.

72 Background: The integration of biopsychosocial screening programs (BSP) has been promoted as a way by which to identify unmet needs and to provide tailored treatments to patients. Studies have reported mixed outcomes regarding the impact of such services on hospital admissions during cancer treatment. This study sought to evaluate the effect of a BSP on hospital admissions and length of stay among a large, heterogenous sample of patients diagnosed with cancer (March 2020 to December 2021). Methods: We enrolled consecutive patients diagnosed with cancer receiving treatment at a single institution located in the capital of Brazil. We assessed patients’ characteristics via chart review (e.g., age, sex, histology, hospital admission, length of hospitalization). In addition, as per the BSP protocol, patients were assessed via standardized self-report questionnaires (Distress Thermometer, FACT-G, Patient-Generated Subjective Global Assessment), and appropriate interventions are provided. This program was offered at no cost to all patients and engagement was voluntary. We compared the number of hospital admissions and length of stay between groups (patients who participated in the BSP vs. those who did not). Mixed linear models adjusted for selected characteristics (age, type of cancer and disease stage) were assessed. Results: A total of 1014 patients were included in this analysis. From the total sample, 84% participated in the BSP and 20% were hospitalized for an average of 9 days (ranging from 1-80 days). Mostly patients were female (63%), median age was 63 years old. Breast cancer (26%), hematological (18%), and gastrointestinal cancer (14%) were the most common types of cancer, and the majority had advanced disease (stage III-IV; 67%). Compared to those who engaged in the BSP, patient’s characteristics were well balanced, however, the proportion of patients hospitalized during their cancer treatment was higher among patients who did not participate in the BSP (27% vs 8%: P = 0.001), as was the length of hospitalization spent more days in the hospital than patients who has participated in the BSP (M = 9.5 days vs M = 4.2 days; P = 0.001). Conclusions: Our findings suggest the benefit of a BSP in reducing hospitalizations and length of stay among patients with cancer. An integrated model of care may assist in targeting patient’s unmet needs and may positively impact clinical and hospital-based outcomes. This is the first study to evaluate the effects of a BSP among a Brazilian population using real world data.

Objective: The aim of this multicentric registry was to assess the outcomes of “anteRior versus posteRior divisional bRanches Of the hYpogastric artery as distAl landing zone for iLiac branch devices (R3OYAL).” Methods: The main exposure of interest for the purpose of this study was the internal iliac artery (IIA) divisional branch (anterior vs posterior) that was used as distal landing zone. Early endpoints included technical success and adverse events. Late endpoints included survival, primary/secondary IIA patency, and IIA branch instability. Results: A total of 171 patients were included in the study, of which 50 received bilateral implantation of iliac branch devices (IBDs). This resulted in a total of 221 incorporated IIAs included in the final analysis, of which 40 were anterior divisional branches and 181 were posterior divisional branches. Technical success was high in both groups (anterior division: 98% vs posterior division: 100%, P = .18). Occurrence of any adverse event was noted in 14% of patients in both groups ( P = 1.0). The overall rate of freedom from the composite IBD branch instability did not show significant differences between patients receiving distal landing in the anterior or posterior division of the IIA at 3 years (79% vs 87%, log-rank test = .215). The 3-year estimates of IBD patency were significantly lower in patients who received distal landing in the anterior divisional branch than those who received distal landing in the posterior divisional branch (primary patency: 81% vs 96%, log-rank test = .009; secondary patency: 81% vs 97%, log-rank test < .001). Conclusions: The use of the anterior or posterior divisional branches of the IIA as distal landing zone for IBD implantation shows comparable profiles in terms of immediate technical success, perioperative safety, and side-branch instability up to 3 years. However, IBD patency at 3 years was higher when the distal landing zone was achieved within the posterior divisional branch of the IIA. Clinical Impact The results from this large multicentric registry confirm that use of the anterior or posterior divisional branches of the internal iliac artery (IIA) as distal landing zone for implantation of iliac branch devices (IBD) shows comparable profiles of safety and feasibility, thereby allowing to extend the indications for endovascular repair of aorto-iliac aneurysms to cases with unsuitable anatomy within the IIA main trunk. Although mid-term rates of device durability and branch instability seem to be similar, the rates of primary and secondary IBD patency at three years was favored when the distal landing zone was achieved in the posterior divisional branch of the IIA.

Objective: To assess outcomes of fenestrated-branched endovascular aortic repair (FB-EVAR) of Extent I-III thoracoabdominal aortic aneurysms (TAAAs) without prophylactic cerebrospinal fluid drainage (CSFD). Background: Prophylactic CSFD has been routinely used during endovascular TAAA repair, but concerns about major drain-related complications have led to revising this paradigm. Methods: We reviewed a multicenter cohort of 541 patients treated for Extent I-III TAAAs by FB-EVAR without prophylactic CSFD. Spinal cord injury (SCI) was graded as ambulatory (paraparesis) or nonambulatory (paraplegia). Endpoints were any SCI, permanent paraplegia, response to rescue treatment, major drain-related complications, mortality, and patient survival. Results: There were 22 Extent I, 240 Extent II and 279 Extent III TAAAs. Thirty-day mortality was 3%. SCI occurred in 45 patients (8%), paraparesis occurring in 23 (4%) and paraplegia in 22 patients (4%). SCI was more common in patients with Extent I-II compared with Extent III TAAAs (12% vs. 5%, P=0.01). Rescue treatment included permissive hypertension in all patients, with CSFD in 22 (4%). Symptom improvement was noted in 73%. Twelve patients (2%) had permanent paraplegia. Two patients (0.4%) had major drain-related complications. Independent predictors for SCI by multivariate logistic regression were sustained perioperative hypotension [odds ratio (OR): 4.4, 95% confidence interval (95% CI): 1.7–11.1], patent collateral network (OR: 0.3, 95% CI: 0.1–0.6), and total length of aortic coverage (OR: 1.05, 95% CI: 1.01–1.10). Patient survival at 3 years was 72%±3%. Conclusion: FB-EVAR of Extent I-III TAAAs without CSFD has low mortality and low rates of permanent paraplegia (2%). SCI occurred in 8% of patients, and rescue treatment improved symptoms in 73% of them.

Objective: To assess the impact of secondary intervention (SI) on health-related quality of life (HR-QOL) after fenestrated-branched endovascular aortic repair (FB-EVAR) for complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. Background: The effect of SI after FB-EVAR on physical and mental HR-QOL has not been described. Methods: A cohort of 430 consecutive patients enrolled in a prospective, nonrandomized study to evaluate FB-EVAR (2013–2020) was assessed with 1325 short-form 36 HR-QOL questionnaires preoperatively and during follow-up visits. SIs were classified as major or minor procedures. Endpoints included patient survival, freedom from aortic-related mortality (ARM), freedom from SIs, and changes in HR-QOL physical component score (PCS) and mental component score. Results: There were 302 male with mean age 74±8 years treated by FB-EVAR for 133 complex abdominal aortic aneurysms and 297 thoracoabdominal aortic aneurysms. After a mean follow up of 26±20 months, 97 patients (23%) required 137 SIs. At 5 years, freedom from any SI was 64%±4%, including freedom from minor SIs of 77%±4% and major SIs of 87%±3%. There was no difference in patient survival and freedom from ARM at same interval. On adjusted analysis, minor SIs correlated with improved survival. SIs had a negative correlation with PCS (r=−0.8). There were no significant changes in mental component score with SIs. Predictors for SIs were fluoroscopy time, graft design, and aneurysm sac change. Conclusion: SIs were needed in nearly 1 out of 4 patients treated by FB-EVAR with no effect on patient survival or ARM. SI resulted in decline in PCS.

INTRODUCTION: Peptic ulcer disease (PUD) is a common cause of hospitalization worldwide. We assessed temporal trends in hospitalization for PUD in 36 Organisation for Economic Co-operation and Development (OECD) countries since the turn of the 21st century. METHODS: The OECD database contains data on PUD-related hospital discharges and mortality for 36 countries between 2000 and 2019. Hospitalization rates for PUD were expressed as annual rates per 100,000 persons. Joinpoint regression models were used to calculate the average annual percent change (AAPC) with 95% confidence intervals (CIs) for each country, which were pooled using meta-analyses. The incidence of PUD was forecasted to 2021 using autoregressive integrated moving average and Poisson regression models. RESULTS: The overall median hospitalization rate was 42.4 with an interquartile range of 29.7–60.6 per 100,000 person-years. On average, hospitalization rates (AAPC = −3.9%; 95% CI: −4.4, −3.3) and morality rates (AAPC = −4.7%; 95% CI: −5.6, −3.8) for PUD have decreased from 2000 to 2019 globally. The forecasted incidence of PUD hospitalizations in 2021 ranged from 3.5 per 100,000 in Mexico to 92.1 per 100,000 in Lithuania. Across 36 countries in the OECD, 329,000 people are estimated to be hospitalized for PUD in 2021. DISCUSSION: PUD remains an important cause of hospitalization worldwide. Reassuringly, hospitalizations and mortality for PUD have consistently been falling in OECD countries in North America, Latin America, Europe, Asia, and Oceania. Identifying underlying factors driving these trends is essential to sustaining this downward momentum.

Objective: Percutaneous femoral artery access is being increasingly used in endovascular aortic repair (EVAR). The technique can be challenging in patients with previously surgically exposed or repaired femoral arteries because of excessive scar tissue. However, a successful percutaneous approach may cause less morbidity than a “re-do” open femoral approach. The aim of this study was to assess the impact of prior open surgical femoral exposure on technical success and clinical outcomes of percutaneous approach. Methods: This study retrospectively reviewed the clinical data of patients who underwent percutaneous EVAR between 2010 and 2020 at 2 major aortic centers. Patients were divided into 2 groups (with or without prior open surgical femoral access) for analysis of clinical outcomes. Only punctures with sheaths ≥12Fr were included for analysis. The access and (pre)closure techniques were similar in both institutions. Primary end points were intraoperative technical success, access-related revision, and access complications. A multivariate analysis was performed to identify determinants of conversion to open approach and femoral access complications in intact and re-do groins. Results: A total of 632 patients underwent percutaneous (complex) EVAR: 98 had prior open surgical femoral access and 534 patients underwent de novo femoral percutaneous access. A total of 1099 femoral artery punctures were performed: 149 in re-do and 950 in intact groins. The extent of endovascular repair included 159 infrarenal, 82 thoracic, 368 fenestrated/branched, and 23 iliac branch devices. No significant differences were seen in technical success (re-do 93.3% vs intact 95.3%, p=0.311), access-related surgical revision (0.7% vs 0.6%, p=0.950), and access complications (2.7% vs 4.0%, p=0.443). For the whole group, significant predictors for access complications in multivariate analyses were main access site (odds ratio [OR] 2.39; 95% confidence interval [CI] 1.07%–5.35%; p=0.033) and increase of the procedure time per hour (OR 1.65; 95% CI 1.34%–2.04%; p<0.001), while increase in sheath-vessel ratio had a protective effect (OR 0.33; 95% CI 0.127%–0.85%; p=0.021). Surgical conversion was predicted by main access site (OR 2.32; 95% CI 1.28%–4.19%; p=0.007) and calcification of 50% to 75% of the circumference of the access vessel (OR 3.29; 95% CI 1.38%–7.86%; p=0.005). Conclusion: Within our population prior open surgical femoral artery exposure or repair had no negative impact on the technical success and clinical outcomes of percutaneous (complex) endovascular aortic aneurysm repair.